Therapeutic Efficacy of a Novel Pharmacologic GRK2 Inhibitor in Multiple Animal Models of Heart Failure.

Overview

GRK2 is the most prominent G protein-coupled receptor kinase that is upregulated in heart failure (HF), and inhibiting GRK2 has improved cardiac function in mice. CCG258208, generated from the paroxetine scaffold, which has GRK2 inhibitory properties, has a 50-fold higher selectivity for GRK2 at 100-fold lower doses. We evaluated CCG258208 in 2 mice HF models and found that CCG258208 has robust therapeutic effects. In a chronic mini-swine HF model, acute administration of CCG258208 enhanced dobutamine inotropic responses. Our results indicate that CCG258208 has robust cardioprotective and HF-reversing effects in different HF models and it stands as a promising lead for HF therapy.